WO2017174758A1 - Association d'un antagoniste de l'apeline et d'un inhibiteur de l'angiogenèse pour le traitement du cancer - Google Patents

Association d'un antagoniste de l'apeline et d'un inhibiteur de l'angiogenèse pour le traitement du cancer Download PDF

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WO2017174758A1
WO2017174758A1 PCT/EP2017/058316 EP2017058316W WO2017174758A1 WO 2017174758 A1 WO2017174758 A1 WO 2017174758A1 EP 2017058316 W EP2017058316 W EP 2017058316W WO 2017174758 A1 WO2017174758 A1 WO 2017174758A1
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apelin
antagonist
cancer
receptor antagonist
receptor
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Josef Penninger
Iris URIBESALGO
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Institute of Molecular Biotechnology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/515—Angiogenesic factors; Angiogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the field of the present invention is the field of anti- angiogenic cancer therapy, especially anti-angiogenic breast or lung cancer therapy.
  • Cancer is the second leading cause of mortality in Europe.
  • Activating angiogenesis the sprouting of new blood vessels from the existing vasculature, is one of the hallmarks of cancer and facilitates rapid tumour growth and metastasis (Hanahan and Weinberg, 2011).
  • inhibiting tumour neo-angiogenesis is a strategy for cancer treatment currently being pursued.
  • VEGF vascular endothelial growth factor
  • Avastin® bevacizumab
  • RTK receptor tyrosine kinase
  • VEGFR VEGF receptor
  • sunitinib sunitinib
  • sorafenib sorafenib
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an apelin antagonist and/or an apelin receptor antagonist.
  • the composition further comprises an angio- genesis inhibitor selected from the group of receptor tyrosine kinase (RTK) inhibitors.
  • RTK receptor tyrosine kinase
  • a combination of apelin antagonist (and/or apelin receptor antagonist) and RTK inhibitor is also called “the inventive combination”.
  • the invention also relates to a method for prevention or treatment of cancer in a patient.
  • the method comprises admin ⁇ istration an effective amount of an apelin antagonist and/or apelin receptor antagonist to the patient.
  • an angi- ogenesis inhibitor preferably selected from the group of RTK inhibitors, is administered to the patient in an effective amount, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is adminis ⁇ tered, or after the apelin antagonist and/or apelin receptor antagonist has been administered.
  • a set comprising the inventive combination in separate pharmaceutical compositions, and said apelin antagonist and/or apelin receptor antagonist for use in the prevention or treatment of cancer in a patient together with an angiogenesis inhibitor are provided. Furthermore, an an ⁇ giogenesis inhibitor for use in the prevention or treatment of cancer in a patient together with said apelin antagonist and/or apelin receptor antagonist is provided.
  • Apelin is an evolutionary conserved peptide that acts as the endogenous ligand for the G-protein-coupled APJ receptor (Tatemoto et al . , 1998), also called apelin receptor.
  • the ape- lin/APJ signalling pathway has been previously shown to play a role in angiogenesis (Kidoya and Takakura, 2012) .
  • Apelin is an angiogenic factor involved in vascular development (Cox et al . , 2006; Kasai et al . , 2008; Kalin et al . , 2007; Saint-Geniez et al . , 2002) and homoeostasis (del Toro et al .
  • Apelin has also been suggested to have a role in the aetiology of obesity (Rayalam et al . , 2008) . Apelin has been found to be up-regulated in certain mouse and human tumours (Berta et al . , 2010; Sorli et al . , 2007) . Wang et al . , 2008, relates to the immunohistochemi- cal localization of apelin in human normal breast and breast carcinoma.
  • apelin is expressed in normal, non-lactating breast tissue as well as in breast carcinoma.
  • Re ⁇ sults from xenograft studies suggest that apelin over-expression in cancer cells affects the vascular component of the tumour by a paracrine action on endothelial cells of the host vessels (Berta et al . , 2010; Sorli et al . , 2007) .
  • Similar results have been reported following VEGF over-expression (Graeven et al . , 2001), which plays a key role in tumour angiogenesis.
  • US 2006/045880 Al relates to methods for modulating angiogen ⁇ esis and apoptosis with apelin compositions.
  • a method for inhib ⁇ iting tumorigenesis with an apelin inhibitor such as an anti- apelin antibody is disclosed.
  • RTK inhibitors are well-known in the art as angiogenesis in ⁇ hibitors, and they differ from VEGF antagonists such as the mon ⁇ oclonal antibody bevacizumab which form a distinct class of an- giogenesis inhibitors (see e.g. Jeltsch et al, 2013) .
  • VEGF antagonists such as the mon ⁇ oclonal antibody bevacizumab which form a distinct class of an- giogenesis inhibitors (see e.g. Jeltsch et al, 2013) .
  • RTK inhibitors act inside the cell, specifically inhibiting the ki ⁇ nase activity of an RTK by binding to the kinase domain of the RTK.
  • RTK inhibitors are small mol ⁇ ecules (i.e. having a molecular weight below 800 Da) able to lo ⁇ calise within cells (e.g. by diffusion), in particular ATP analogues with limited specificity.
  • RTK inhibitors are distinct from VEGF antagonists such as bevacizumab and discusses the mechanism of RTK inhibitors.
  • the RTK inhibitor can be any pharmaceutically acceptable, anti-angiogenic RTK inhibitor such as so-called "multikinase in ⁇ hibitors".
  • Suitable RTK inhibitors are also disclosed e.g. in WO 2001/060814 A2, WO 2002/059110 Al, WO 2003/068228 Al, US 6534524 Bl and US 7141581 B2, and in Bukowski et al . , 2012 and Bhargava et al. 2011.
  • the RTK inhibitor is a pharmaceutically accepta ⁇ ble RTK inhibiting the kinase activity of (in particular human) VEGFR-1, VEGFR-2, VEGFR-3 and/or VEGFR-4, and/or inhibiting the kinase activity of (in particular human) platelet-derived growth factor receptor ( PDGFR) -alpha and/or PDGFR-beta.
  • PDGFR platelet-derived growth factor receptor
  • the RTK inhibitor has a half maximal inhibi ⁇ tory concentration (IC 50 ), in respect to one or more of (in par ⁇ ticular human) VEGFR-1, VEGFR-2, VEGFR-3 and VEGFR-4, below 1000 nM, preferably below 500 nM, more preferably below 200 nM, even more preferably below 100 nM, especially below 50 nM or even be ⁇ low 10 nM in a cell-free assay.
  • IC 50 half maximal inhibi ⁇ tory concentration
  • the RTK inhibitor has an IC 50 , in respect to one or more of (in particular human) PDGFR alpha and PDGFR beta, below 1000 nM, preferably below 500 nM, more preferably below 200 nM, even more preferably below 100 nM, especially below 50 nM or even below 10 nM in a cell-free assay.
  • said cell-free assay is performed as disclosed in Sun et al . , 1999, in particular in the sections "PDGF-R and EGF- R Kinase Assays” and “FGF-R1 and Flk-l/KDR Kinase Assays", op ⁇ tionally with modifications immediately apparent to the person skilled in the art (such as appropriately changing the receptor tyrosine kinase to be tested or the antibody binding thereto) .
  • the RTK inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib.
  • sunitinib, sorafenib, pazopanib and axitinib are especially pre ⁇ ferred, among them sunitinib is particularly suitable for the present invention because it shows exceptionally strong thera ⁇ Commissionic benefit in combination with apelin inhibition.
  • the human APLN gene codes for an apelin preproprotein with 77 amino-acid residues ("apelin-77”; UniProt accession code Q9ULZ1, sequence version: 1) containing a signal peptide in its amino-terminal sequence thus directing apelin in the secretory pathway (see e.g. Chaves-Almagro et al, 2015; especially Fig. 1 thereof).
  • apelin-55 the proprotein
  • apelin-55 gives rise to several bioactive carboxy-terminal fragments including apelin-36, apelin-17 and apelin-13.
  • the ami- no-terminal glutamine of apelin-13 can be post-translationally modified thus creating the pyroglutamate apelin-13 (pyr-apelin- 13) which is more protected from exopeptidase degradation.
  • An overview of human apelin variants is given in Fig. 1 (which is derived from Table 1 of Chapman et al . , 2014) .
  • the murine apelin preproprotein (UniProt accession code Q9R0R4, sequence version: 1) has the same length as the human homolog (i.e. murine apelin-77) and is highly similar, with an amino-acid identity of more than 80% to human apelin-77.
  • the apelin antago ⁇ nist can be any compound that specifically binds apelin and re ⁇ Jerusalem or inhibits binding of apelin to the apelin receptor, e.g. by steric hindrance, or by reducing apelin stability e.g. in an extracellular body fluid such as blood serum.
  • the apelin antagonist is specific for one or more of apelin-77, ape- lin-55, apelin-36, apelin-17, pyr-apelin-13, apelin-13 and ape- lin-12 as defined in Fig. 1.
  • the apelin antagonist is an anti-apelin antibody, in particular a monoclonal anti- apelin antibody.
  • the, preferably monoclonal, anti ⁇ body is specific for one or more of apelin-77, apelin-55, ape ⁇ lin-36, apelin-17, pyr-apelin-13, apelin-13 and apelin-12 as de ⁇ fined in Fig. 1, especially one or more of apelin-36, apelin-17, pyr-apelin-13 and apelin-13.
  • Suitable epitopes can be predicted by methods known in the art, e.g. by the method of Larsen et al. 2006, which is also conveniently available for the skilled per ⁇ son as an online tool e.g.
  • the, preferably monoclonal, anti-apelin antibody is specific for one or more of the following peptide epitopes: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 consecutive amino acids selected from the amino acid sequence VQPRGSRNGPGPWQG- GRRKFR (SEQ ID NO: 8), preferably 5, 6, 7, 8, 9, 10, 11 or 12 consecutive amino acids selected from the amino acid sequence RGSRNGPGPWQG (SEQ ID NO: 9), especially 5, 6 or 7 consecutive amino acids selected from the amino acid sequence RNGPGPW (SEQ ID NO: 10); or 5, 6, 7, 8, 9, 10 or 11 consecutive amino acids selected from the amino acid sequence PRLSHKGPMPF (SEQ ID NO: 11), preferably 5, 6 or 7 consecutive amino acids selected from the amino acid sequence PRLSHKG (SEQ ID NO: 12) or 5, 6, 7 or 8 consecutive amino acids selected from the amino acid sequence LSHKGPMP (SEQ ID NO: 8), preferably 5, 6 or 7 consecutive amino acids selected from the amino acid sequence PRLSHKG (SEQ ID
  • anti-apelin antibodies suitable for the present inven ⁇ tion are known in the prior art.
  • the WO 2013/012855 Al discloses a monoclonal anti-apelin antibody spe ⁇ cific for the epitope PRLSHKG (SEQ ID NO: 12; present in all forms of apelin shown in Fig. 1) that is particularly suitable for the present invention.
  • Another suitable monoclonal antibody, specific for at least the apelin-13 form is disclosed e.g. in Kawamata et al . , 2001.
  • Suitable polyclonal antibodies raised against apelin-17 are disclosed e.g. in Reaux et al . , 2002.
  • Suitable anti-apelin antibodies are for instance also commer- cially available from Santa Cruz Biotechnology Inc. (Dallas, TX, USA) or Abeam pic (Cambridge, UK) .
  • the monoclonal anti-apelin antibody is preferably humanised.
  • Methods to obtain humanised antibodies are well known in the art.
  • One method is to insert the variable regions of the anti ⁇ body (e.g. the variable regions of the monoclonal antibody dis ⁇ closed in the WO 2013/012855 Al, especially Fig. 1 thereof) into a human antibody scaffold.
  • monoclonal antibodies can also be raised in genetically modified mice, such as the VELOCIMMUNE® mouse; see e.g. the US patents no. 6,596,541 and US 7,105,348.
  • the human APLNR gene (NCBI Entrez Gene ID: 187) codes for the human apelin receptor (cf. Chaves-Almagro et al, 2015; especial ⁇ ly Fig. 2 thereof) .
  • the gene encodes a protein of 380 amino ac ⁇ ids (UniProt accession code P35414, sequence version: 1) which belongs to the class A (rhodopsin-like receptor) G protein- coupled receptor (GPCR) family.
  • Glu20 and Asp23 in the extracel ⁇ lular N-terminal tail were first identified as crucial residues for binding of its endogenous ligand apelin.
  • Asp94, Glul74 and Asp284 are also in ⁇ volved in apelin binding.
  • the apelin receptor antagonist can be any compound that specifically binds apelin receptor and reduces or inhibits binding of apelin to the apelin receptor, e.g. by steric hindrance, or by reducing apelin recep ⁇ tor stability.
  • the apelin receptor antagonist is specific for human apelin receptor.
  • the apelin receptor antagonist is an anti-apelin-receptor anti- body, in particular a monoclonal anti-apelin-receptor antibody.
  • Suitable epitopes can be predicted by methods known in the art, e.g. by the method of Larsen et al . 2006, which is also conven ⁇ iently available for the skilled person as an online tool e.g. on http://tools.iedb.org/bcell/ and also provides other epitope prediction methods) .
  • the epitope includes at least one of the amino acid sites of the receptor known to be involved in apelin binding, in particular selected from Glu20, Asp23, Asp94, Glul74 and Asp284 (according to the numbering of UniProt accession code P35414, sequence version: 1).
  • the, preferably monoclonal, anti-apelin-receptor antibody is specific for one or more of the following peptide epitopes: 5, 6, 7, 8,
  • Anti-apelin-receptor antibodies suitable for the present invention are known in the prior art. Anti-apelin-receptor antibodies are for instance disclosed in WO 1999/033976 Al . Also suitable for the present invention is the monoclonal anti- apelin-receptor antibody MAB856 disclosed in Puffer et al . , 2000. This antibody is commercially available as MAB856 from R&D Systems, Inc., Minneapolis, MN, USA. Especially suitable for the present invention is an antibody, antibody-fusion protein or antigen-binding fragment as claimed in any one of claims 1-14 of the WO 2015/077491 Al, especially when the sequence specified in the claims (cf.
  • Table 1 of WO 2015/077491 Al is drawn to any one of H1M9207N, H2aM9209N, H2aM9222N, H2aM9227N, H2aM9228N, H2aM9230N and H2aM9232N, in particular to H2aM9232N.
  • the monoclonal anti-apelin-receptor antibody is preferably humanised .
  • the apelin receptor antagonist is an apelin analogue.
  • the apelin analogue is structurally similar to apelin and inhibits activa ⁇ tion of the apelin receptor by apelin. Preferably the inhibition is by competing with apelin for the apelin binding site on the receptor.
  • the analogue decreases apelin- induced apelin receptor activation by a factor of at least 3, preferably of at least 5, more preferably of at least 10, espe ⁇ cially of at least 50.
  • Apelin receptor activation can be measured in vitro or in vivo, as e.g. disclosed in Chaves-Almagro et al . , 2015, especially p. 152, section 2.5; in particular by measuring decrease of mean arterial blood pressure in anaesthe ⁇ tized rats (see Lee et al, 2005; in particular Fig. 3B and sec ⁇ tion "Blood pressure and heart rate bioassay") or according to the cyclic AMP assay disclosed in Example 5 of the WO 2015/077491 Al . It is preferred that the apelin analogue is a peptide.
  • the apelin analogue is the peptide apelin F13A (QRPRLSHKGPMPA; SEQ ID NO: 14) .
  • Apelin F13A was characterized e.g. in Lee et al, 2005.
  • the apelin analogue can also be the peptide ALX40-4C (N- -acetyl-nona-D-arginine am ⁇ ide; SEQ ID NO: 22) which was characterized e.g. in Zhou et al, 2003, although higher sequence identity of the antagonist to apelin (e.g.
  • apelin-36 or apelin-13 is preferred to increase specificity for the apelin receptor (of course, while still re ⁇ taining its antagonistic property in regard to the apelin recep ⁇ tor, e.g. by appropriate point mutations such as in the case of apelin F13A) , e.g. at least 50% sequence identity, preferably at least 60% sequence identity, more preferably at least 70% se ⁇ quence identity, even more preferably at least 80% sequence identity, in particular at least 90% sequence identity.
  • apelin receptor antagonists suitable for the present invention are also known in the art: For instance, Macaluso et al., 2011, discloses cyclo ( 1- 6) CRPRLC-KH-cyclo ( 9-14 ) CRPRLC (SEQ ID NO: 23) as a competitive antagonist of apelin receptor.
  • the apelin receptor antagonist 4-oxo-6- ( (pyrimidin-2-ylthio) methyl) - 4H-pyran-3-yl 4-nitrobenzoate (ML221) is disclosed e.g. in Malo- ney et al, 2012.
  • Further suitable apelin receptor antagonists are disclosed e.g. in the US 2014/0005181 Al, the WO 2010/053545 A2 and the WO 2014/044738 Al .
  • Further apelin antagonists or ape ⁇ lin receptor antagonists are disclosed in WO 2015/140296 A2.
  • the inventive combination can be provided as a set or kit-of-parts . Therefore, the present invention is drawn, in a further aspect, to a set comprising a first pharma ⁇ ceutical composition and a second pharmaceutical composition.
  • the first pharmaceutical composition comprises the apelin antag ⁇ onist and/or the apelin receptor antagonist.
  • the second pharma ⁇ ceutical composition comprises the angiogenesis inhibitor se ⁇ lected from the group of RTK inhibitors.
  • the set is advanta ⁇ geously provided in the same packaging, wherein the first compo ⁇ sition is in a first container (e.g. in liquid form) and the second composition is in a second container (e.g. in tablet form) .
  • the invention relates to an apelin antagonist and/or apelin receptor antagonist, or an angiogenesis inhibitor, for use in the prevention or treatment of cancer in a patient.
  • the apelin antagonist and/or apelin receptor antagonist is administered to the patient.
  • An angiogenesis inhibitor, pref ⁇ erably selected from the group of RTK inhibitors, is adminis ⁇ tered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is administered, or after the apelin antagonist and/or apelin receptor antagonist has been administered.
  • an apelin antagonist and/or apelin receptor antagonist being administered to the patient, in a composition together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibitor is administered, or after the angiogenesis inhibitor has been ad ⁇ ministered.
  • the inventive treatment is for increas ⁇ ing drug delivery (e.g. of a further chemotherapeutic agent), reducing tumour growth (either an absolute reduction of mass, or a reduction of mass increase per time interval) , preventing ma ⁇ lignancy and/or preventing metastasis (in particular metastasis induced by anti-angiogenic treatment, e.g. with an RTK inhibitor such as sunitinib) .
  • the tumour to be treated is a solid tumour.
  • the invention relates to an apelin antagonist and/or apelin receptor antagonist (or an angiogenesis inhibitor) for use in the prevention or treatment of metastasis in a cancer patient, wherein the patient has undergone or is un ⁇ dergoing cancer treatment with an angiogenesis inhibitor (or an apelin antagonist and/or apelin receptor antagonist).
  • an apelin antagonist and/or apelin receptor antagonist or an angiogenesis inhibitor
  • an angiogenesis inhibitor or an apelin antagonist and/or apelin receptor antagonist
  • the invention relates to an apelin antagonist and/or apelin receptor antagonist for use in the treat ⁇ ment of a cancer patient who has resistance or is at risk of de ⁇ veloping resistance to anti-angiogenic therapy.
  • This aspect also relates to an angiogenesis inhibitor for use in the treatment of a cancer patient who has resistance or is at risk of developing resistance to anti-angiogenic therapy, wherein the angiogenesis inhibitor is administered to the patient, and wherein an apelin antagonist and/or apelin receptor antagonist, is administered to the patient, in a composition together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibitor is administered, or after the angio ⁇ genesis inhibitor has been administered.
  • Resistance to anti-angiogenic therapy can be characterized by non-responsiveness of the cancer patient's tumour or relapse af ⁇ ter an initial response, as described for instance in Bergers et al . , 2008 and Jayson et al, 2016.
  • non-responsiveness is defined as fulfilling the criteria for "stable disease” or "progressive disease” (in particular the latter) according to the version 1.1 of RECIST guidelines (Eisenhauer et al . , 2009, in particular item 4.3.1 thereof) after having been (e.g.
  • relapse is defined as ful ⁇ filling the criteria for "progressive disease" according to ver- sion 1.1 of the RECIST guidelines (Eisenhauer et al . , 2009, in particular item 4.3.1 thereof), after the criteria for "complete response” or "partial response” (especially the former) had ini ⁇ tially been fulfilled according to said guidelines (see Eisen ⁇ hauer et al . , 2009, in particular item 4.3.1 thereof) upon (e.g. at least 2 weeks, preferably at least 4 weeks, more preferably at least 8 weeks, even more preferably at least 12 weeks, espe ⁇ cially at least 16 weeks or even at least 24 weeks) anti- angiogenic treatment.
  • a cancer patient is at risk of developing resistance to anti-angiogenic therapy if the tumour/cancer is Kras-positive (as defined above) , over-expresses granulocyte- colony stimulating factor (G-CSF) (compared to an appropriate control), and/or over-expresses P-Rexl (compared to an appropri ⁇ ate control), see e.g. Phan et al . , 2013 and Goel et al, 2016.
  • G-CSF granulocyte- colony stimulating factor
  • P-Rexl compared to an appropri ⁇ ate control
  • a cancer patient is, in particular, at risk of developing resistance to anti-angiogenic therapy if obese (i.e. the patient has a body mass index of at least 30 kg/m 2 , especially at least 35 kg/m 2 ) , see e.g. Incio et al, 2015.
  • the an- giogenesis inhibitor can also be a VEGF antagonist such as the monoclonal antibody bevacizumab.
  • a VEGF antagonist such as the monoclonal antibody bevacizumab.
  • an RTK inhibitor is not a VEGF antagonist
  • sunitinib is preferred as it is particu ⁇ larly effective.
  • the VEGF antagonist can be any compound that specifically binds VEGF and reduces or inhibits binding of VEGF to the VEGF receptor, e.g. by steric hindrance, or by reducing VEGF stability e.g. in an extracellular body fluid such as blood serum.
  • anti-VEGF antibodies such as bevacizumab and ranibizumab
  • VEGF traps such as afliber- cept
  • the cancer to be treated or prevented is selected from breast cancer, lung cancer, ovarian cancer, cervi- cal cancer, hepatocellular carcinoma, renal cell carcinoma (RCC) , especially clear-cell RCC, thyroid cancer, neuroendocrine cancer, gastro-oesophageal cancer, colorectal cancer, glioma, prostate cancer and pancreatic cancer.
  • the cancer can be of epithelial origin (i.e. carcinoma or epithelial cancer) .
  • the patient has a loss-of-function mutation or deletion of one or more of the genes BRCA1, BRCA2, BRCA3 and RAD51D.
  • the present invention is particularly effective in breast cancer and lung cancer, as shown in particular in Fig. 3 and 4.
  • the cancer is selected from breast cancer and lung cancer (especial ⁇ ly non-small cell lung cancer) .
  • the cancer is of epi ⁇ thelial origin (i.e. carcinoma or epithelial cancer).
  • cancers that are HER-2-positive (see Fig. 3b; Neu is the rodent homolog of HER-2, with NeuT being a particu ⁇ larly oncogenic form thereof), p53-negative (see also Fig. 4b), KRas- positive (see also Fig. 4b), estrogen-receptor- (ER) -positive (see also Fig. 10, the human breast cancer cell line E0771 is ER-positive) , or combinations thereof. Therefore, in a further preference, the cancer is HER-2-positive (i.e.
  • over-expressing HER-2 compared to healthy control tissue over-expressing HER-2 compared to healthy control tissue
  • p53-negative i.e. not expressing p53 or under-expressing p53 compared to healthy control tissue or having mutated p53
  • Kras-positive i.e. over- expressing KRas compared to healthy control tissue or having mu ⁇ tated KRas
  • ER-positive i.e. over-expressing ER compared to healthy control tissue
  • the cancer is HER-2-positive, ER-positive and/or p53-negative breast cancer (or HER-2-negative, p53-negative and/or ER-positive breast cancer); or HER-2-positive and/or p53-negative and/or KRas-positive lung cancer (especially non-small cell lung can ⁇ cer) .
  • the oncogene (or tumour suppressor) status of a cancer can be tested e.g. by immunohistochemistry (IHC) or fluorescence in- situ hybridisation; testing for oncogene (or tumour suppressor) status of a cancer is well-established clinical practice.
  • status of HER-2, ER, KRas and p53 is defined in the following way:
  • the cancer is HER2-positive when an intense and uniform complete HER-2 mem ⁇ brane staining is observed in more than 10% of the invasive tu ⁇ mour cells in an IHC assay, and/or, in an in-situ hybridisation assay such as FISH or bright field ISH, when the dual-probe HER2/CEP17 ratio is at least 2.0 or the average HER2 copy number is at least 6.0 signals per cell; in particular as disclosed in Rakha et al . , 2015, especially Fig. 1 thereof.
  • the cancer is ER- positive when it has an Allred score of at least 3 (the Allred scoring system is disclosed e.g. in Harvey et al . , 1999). Guide ⁇ lines for immunohistochemical testing of ER are for instance given in Hammond et al . , 2010.
  • the cancer is Kras-positive when it harbours a mutation in the KRas gene or protein (see e.g. van Cutsem et al . , 2009 for testing methods), preferably leading to a KRas protein with higher GTPase activity than wild-type KRas.
  • the cancer is p53-negative when it does not have p53 gene or protein or harbours a mutation in the p53 gene or protein interfering with wild-type p53 function.
  • the present invention has been shown to effectively reduce expression of epithelial-mesenchymal transition (EMT) markers and invasiveness-related genes (see Fig. 9b) .
  • EMT epithelial-mesenchymal transition
  • invasiveness-related genes see Fig. 9b
  • the cancer over- expresses EMT markers and/or over-expresses invasiveness-related genes (compared to an appropriate control, e.g. healthy adjoin ⁇ ing tissue) .
  • Suitable EMT markers are known from e.g. Lamouille et al . 2014, in particular Table 1.
  • the EMT marker used is selected from the group of Snail (especially SNAIL1 and SNAIL2), fibronectin (especially fibronectin 1), and TGF-beta.
  • Suitable invasiveness-related genes are known from e.g. Ho-Yen et al . , 2015, Martin et al . , 2013, Gherardi et al, 2012, Apte et al . , 2006, and Kalluri, et al . , 2006.
  • the invasive ⁇ ness-related gene is selected from the group of Met, ILlb, COL1A1 and COL1A2.
  • the present invention is extraordinarily effective in cancers that over-express apelin or apelin receptor.
  • the cancer over- expresses apelin and/or apelin receptor (compared to an appropriate control, e.g. healthy adjoining tissue).
  • a further preferred embodiment of the present invention re ⁇ lates to the apelin antagonist and/or apelin receptor antago ⁇ nist, or the angiogenesis inhibitor, for use, wherein a further chemotherapeutic agent is administered to the patient, in a com ⁇ position together with the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, in combination with the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, before the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, is administered, or after the apelin antagonist and/or apelin re ⁇ ceptor antagonist, or the angiogenesis inhibitor, has been ad ⁇ ministered.
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics.
  • the further chemotherapeutic agent is selected from the group of 5- fluorouracil , cisplatin, carboplatin, cyclophosphamide, doxoru ⁇ bicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etoposide.
  • Topoisomerase inhibitors are especially preferred, as cancers treated by the inventive combination are particularly sensitive to this additional treatment (see Fig. 9d) .
  • apelin antagonists, apelin recep ⁇ tor antagonists, angiogenesis inhibitors, RTK inhibitors and Src tyrosine kinase inhibitors are not the be understood as "further chemotherapeutic agents”.
  • radiotherapy is administered to the patient, in combination with the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, be ⁇ fore the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, is administered, or after the apelin antagonist and/or apelin receptor antagonist, or the angiogene ⁇ sis inhibitor, has been administered.
  • the tyrosine kinase Src is a cytoplasmic tyrosine kinase en ⁇ coded by the proto-oncogene SRC.
  • Src tyrosine kinase is not an RTK.
  • cancers treated with the inventive combination are particularly sensitive to Src tyrosine kinase inhibitor treat ⁇ ment (see Fig. 9e) .
  • a further preferred embodiment of the present invention relates to the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use, wherein a Src tyrosine kinase inhibitor is administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis in ⁇ hibitor, in combination with the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, before the apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, is administered, or after the apelin an ⁇ tagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, has been administered.
  • Src tyrosine kinase inhibitors are small molecules (i.e. having a molecular weight below 800 Da) able to localise within cells (e.g. by diffusion), in particular ATP analogues with limited specificity.
  • Suitable Src tyrosine kinase inhibi ⁇ tors are for instance described in Rososki 2015 (in particular Table 4 and Fig. 8 thereof) and throughout Schenone, et al . , 2011.
  • the Src tyrosine kinase inhibitor is any pharmaceutically acceptable compound in ⁇ hibiting the kinase activity of the protein Src (in particular human Src), preferably by binding to Src.
  • the Src tyrosine kinase inhibitor has a half maximal inhibitory concentration (IC 50 ) in respect to (in partic ⁇ ular human) Src below 1000 nM, preferably below 500 nM, more preferably below 200 nM, even more preferably below 100 nM, es ⁇ pecially below 50 nM or even below 10 nM in a cell-free assay.
  • IC 50 half maximal inhibitory concentration
  • said cell-free assay is performed as disclosed in WO 2007/014707 Al, in particular on p. 16, line 17 to p. 17, line 20, or as disclosed in WO 02/092573 A2, in particular in the section "Src Inhibition Assays" beginning on p. 47; optionally with modifications immediately apparent to the person skilled in the art.
  • the Src tyrosine kinase inhibitor is preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib.
  • the patient has an apelin level, preferably a plasma or serum apelin level, higher than an appropriate control (such as a healthy age-matched individual or an average of a group of healthy individuals) .
  • an appropriate control such as a healthy age-matched individual or an average of a group of healthy individuals
  • the cancer as measured e.g. in a biopsy of the primary tumour
  • an apelin or apelin receptor level higher than an appropriate control (such as healthy adjoining tissue).
  • the apelin (or apelin receptor) level is measured after the patient has undergone cancer treatment with an angiogenesis inhibitor, preferably selected from the group of RTK inhibitors, especially sunitinib. This can serve to predict anti-angiogenic resistance.
  • said measurement occurs before treatment with the apelin antagonist or apelin receptor antagonist is started.
  • the apelin antagonist or apelin receptor antago ⁇ nist is administered.
  • the threshold can be at 110% of the con ⁇ trol apelin (receptor) level, preferably at 120%, more prefera ⁇ bly at 130%, even more preferably at 140%, especially at 150% or even at 200% or 300%.
  • ELI SA kits for measuring apelin levels are commercially available e.g. from Phoenix Pharmaceuticals, Inc, Burlingame, USA.
  • an aggregate apelin level of apelin-36, apelin-17, apelin-13, pyr-apelin-13 and apelin-12 is measured.
  • the apelin level measured can be selected from one or more of the level of apelin-36, apelin-17, apelin-13, pyr-apelin-13 and apelin-12, preferably from apelin-17, apelin-13, pyr-apelin- 13 and apelin-12, especially from apelin-13 and pyr-apelin-13.
  • the apelin receptor level can be measured for instance with the anti-apelin-receptor antibodies disclosed herein in an ELISA or a immunohistochemistry assay performed e.g. of tumour cells. The skilled person knows how to select an appropriate control or control group in regard to the apelin or apelin receptor level.
  • the control group is (at least essentially) matched for one or more of age, body mass index and sex.
  • the blood sample is taken at a fasting state, e.g. after 12 hours of fasting, for both the patient and the control.
  • the control is the apelin level of the patient, preferably in plasma or serum obtained from the patient, or the apelin receptor level of the (primary) tumour of the patient (e.g. of a tumour sample obtained by biopsy) , before the patient has undergone cancer treatment with the angiogenesis inhibitor, preferably selected from the group of RTK inhibitors, especially sunitinib.
  • the ape ⁇ lin antagonist and/or apelin receptor antagonist is adminis ⁇ tered .
  • tumour blood vessel normalisation in other words: reduction of tumour blood vessel leakiness and/or reduction of interstitial pressure
  • the present invention is for tumour blood vessel normalisation (again, in other words: reduction of tumour blood vessel leakiness and/or reduction of interstitial pressure) .
  • This beneficial effect of the inventive treatment is for instance shown in Figs. 7 and 8.
  • Blood vessel normalisation can be measured by methods known in the art, such as magnetic resonance imaging (MRI) (cf. Fig. 7) and fluores ⁇ cence microscopy of dextran extravasation (cf . Fig. 8) .
  • MRI magnetic resonance imaging
  • fluores ⁇ cence microscopy of dextran extravasation cf . Fig. 8 .
  • the present invention provides a pharma ⁇ ceutical composition
  • a pharma ⁇ ceutical composition comprising an apelin antagonist (as disclosed above) and/or apelin receptor antagonist (as disclosed above) and a further chemotherapeutic agent.
  • This composition is preferably prepared for parenteral, especially intravenous, ad ⁇ ministration.
  • the components can also be provided as a set or kit-of-parts , i.e. a set comprising a first pharma ⁇ ceutical composition comprising an apelin antagonist and/or ape- lin receptor antagonist (as disclosed above) and a second phar ⁇ maceutical composition comprising a further chemotherapeutic agent.
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics.
  • the further chemotherapeutic agent is selected from the group of 5- fluorouracil , cisplatin, carboplatin, cyclophosphamide, doxoru ⁇ bicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etoposide.
  • Topoisomerase inhibitors are especially preferred.
  • apelin antagonists, apelin receptor antagonists, angiogenesis inhibitors, RTK inhibitors and Src tyrosine kinase inhibitors, especially as disclosed herein are not the be understood as "further chemotherapeutic agents”.
  • the composition or set can be used for any one of the therapeutic uses disclosed herein, such as treatment of breast cancer or lung cancer, e.g. in a cancer patient with resistance or at risk of developing resistance to an anti-angiogenic thera ⁇ py.
  • the present invention relates to the further chemotherapeutic agent as defined above for use in treatment of a cancer, or in prevention or treatment of cancer metastasis, in a cancer patient.
  • the patient has undergone or is undergoing or is subsequently to undergo treat ⁇ ment with the angiogenesis inhibitor, in addition to the patient having undergone or undergoing or subsequently to undergo treat ⁇ ment with the apelin antagonist or apelin receptor antagonist.
  • the present invention provides a pharma ⁇ ceutical composition
  • a pharma ⁇ ceutical composition comprising an apelin antagonist (as disclosed above) and/or apelin receptor antagonist (as disclosed above) , or an angiogenesis inhibitor (as disclosed above) , and a Src tyrosine kinase inhibitor.
  • This composition is preferably prepared for oral administration.
  • the components can also be provided as a set or kit-of-parts , i.e.
  • the Src tyrosine kinase inhibitor is preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, sara- catinib and AZD0424, especially dasatinib.
  • This composition or set preferably further comprises an angiogenesis inhibitor (or an apelin antagonist and/or apelin receptor antagonist) as defined herein.
  • the composition or set can be used for any one of the therapeutic uses disclosed herein, such as treatment of breast cancer or lung cancer, e.g. in a cancer patient with resistance or at risk of developing resistance to an anti- angiogenic therapy.
  • the present invention relates to the Src tyrosine kinase as defined herein for use in treatment of a cancer, or in prevention or treatment of cancer metastasis, in a cancer patient.
  • the patient has undergone or is undergoing or is subsequently to undergo treatment with the angiogenesis inhibitor, in addition to the patient having undergone or undergoing or subsequently to undergo treatment with the apelin antagonist or apelin receptor antagonist.
  • the present invention provides an arti ⁇ cle of manufacture enclosing the composition or set as defined in any one of the aspects or embodiments mentioned above, to ⁇ gether with a package insert indicating the use as defined in any one of the aspects or embodiments mentioned above.
  • an article of manufacture (such as a packaging) encloses a pharmaceutical composition comprising an apelin antagonist and/or an apelin receptor antagonist, and further comprising an angiogenesis inhibitor, wherein the angiogenesis inhibitor is selected from the group of RTK inhibitors, together with a package insert indicating use for the treatment of a cancer patient who has resistance or is at risk of develop ⁇ ing resistance to anti-angiogenic therapy with an angiogenesis inhibitor selected from the group of RTK inhibitors.
  • an article of manufacture (such as a packaging) encloses a set comprising a first pharma ⁇ ceutical composition, comprising an apelin antagonist and/or an apelin receptor antagonist, and a second pharmaceutical composi ⁇ tion, comprising an angiogenesis inhibitor, wherein the angio- genesis inhibitor is selected from the group of RTK inhibitors, together with a package insert indicating use for prevention or treatment of cancer in a patient, wherein the cancer is selected from breast cancer and lung cancer, wherein the cancer is HER-2- positive, p53-negative, ER-positive, KRas-positive or combina ⁇ tions thereof.
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the popu ⁇ lation are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occur ⁇ ring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in mi ⁇ nor amounts.
  • polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single de ⁇ terminant on an antigen.
  • the modifier "monoclonal" indi ⁇ cates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybrido- ma method, recombinant DNA methods, phage-, yeast- or mammalian cell-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.
  • preventing means to stop a disease state or condition from occurring in a patient or subject completely or almost completely or at least to a (pref ⁇ erably significant) extent, especially when the patient or sub ⁇ ject is predisposed to such a risk of contracting a disease state or condition.
  • the expression "pharmaceutical composition”, especially if it comprises at least one active agent selected from anti-apelin antibodies, anti-apelin-receptor antibodies, peptide apelin antagonists or peptide apelin receptor antago- nists such as apelin F13A (in an embodiment herein also called the "first pharmaceutical composition”) refers to any composi ⁇ tion comprising the active agent and one or more excipients pharmaceutically acceptable for parenteral administration.
  • Suit ⁇ able excipients are known to the person skilled in the art, for example water (especially water for injection), saline, Ringer's solution, dextrose solution, buffers, Hank solution, vesicle forming compounds (e.g.
  • lipids lipids
  • fixed oils ethyl oleate
  • 5% dextrose in saline substances that enhance isotonicity and chemical stability
  • buffers and preservatives include any compound that does not itself induce the production of antibodies in the patient that are harmful for the patient. Examples are well tolerable proteins, polysaccharides, polylactic acids, polyglycolic acid, polymeric amino acids and amino acid copolymers.
  • This pharmaceutical composition can (as a drug) be administered via appropriate procedures known to the skilled person to a patient in need thereof (i.e. a patient hav ⁇ ing or having the risk of developing the diseases or conditions mentioned herein) .
  • the preferred route of administration of said pharmaceutical composition is parenteral administration, in particular through intravenous, intramuscular or subcutaneous administration.
  • the pharmaceutical composition of the present invention is provided in injectable dosage unit form, eg as a solution, suspension or emulsion, formulated in conjunction with the above-defined pharmaceutically acceptable excipients.
  • injectable dosage unit form eg as a solution, suspension or emulsion, formulated in conjunction with the above-defined pharmaceutically acceptable excipients.
  • the dosage and method of administration depends on the individual patient to be treated.
  • Said pharmaceutical composition especially comprising at least one active agent selected from anti-apelin antibodies, anti-apelin receptor antibodies, anti-apelin receptor antibodies, peptide apelin antagonists or peptide apelin receptor antagonists such as apelin F13A (in an embodiment herein also called the "first pharmaceutical composition” herein)
  • the active agent may be present in the pharmaceutical composition in an amount from 1 mg to 10 g, pref ⁇ erably 50 mg to 2 g, in particular 100 mg to 1 g.
  • Usual dosages can also be determined on the basis of kg body weight of the pa ⁇ tient, for example preferred dosages are in the range of 0.1 mg to 100 mg/kg body weight, especially 1 to 10 mg/kg body weight (per administration session). The administration may occur e.g. once daily, once every other day, once per week or once every two weeks.
  • said phar ⁇ maceutical composition especially comprising at least one ac ⁇ tive agent selected from anti-apelin antibodies, anti-apelin re ⁇ ceptor antibodies, peptide apelin antagonists or peptide apelin receptor antagonists such as apelin F13A (in an embodiment here ⁇ in also called the "first pharmaceutical composition” herein)
  • the pharmaceutical composition ac ⁇ cording to the present invention is preferably liquid or ready to be dissolved in liquid such sterile, de-ionised or distilled water or sterile isotonic phosphate-buffered saline (PBS) .
  • 1000 yg (dry-weight) of such a composition comprises or consists of 0.1-990 yg, preferably l-900yg, more preferably 10- 200yg apelin (receptor) antagonist, and optionally 1-500 yg, preferably 1-100 yg, more preferably 5-15 yg (buffer) salts (preferably to yield an isotonic buffer in the final volume) , and optionally 0.1-999.9 yg, preferably 100-999.9 yg, more pref ⁇ erably 200-999 yg other excipients.
  • 100 mg of such a dry composition is dissolved in sterile, de-ionised/distilled water or sterile isotonic phosphate-buffered saline (PBS) to yield a final volume of 0.1-100 ml, preferably 0.5-20 ml, more preferably 1-10 ml.
  • PBS sterile isotonic phosphate-buffered saline
  • the expression "pharmaceutical com ⁇ position" especially if it comprises at least one active agent selected from RTK inhibitors such as sunitinib, sorafenib, pazo- panib, axitinib, cabozantinib, regorafenib, vandetanib, tivoza- nib, cediranib, nintedanib and vatalanib (in an embodiment here ⁇ in also called the "second pharmaceutical composition”) , refers to any composition comprising the active agent and one or more excipients pharmaceutically acceptable for oral administration. Suitable excipients are known to the person skilled in the art, e.g.
  • inert diluents such as calcium carbonate, sodium car ⁇ bonate, lactose, calcium phosphate or sodium phosphate; granu ⁇ lating and disintegrating agents, e.g. corn starch, or alginic acid; binding agents, e.g. starch, gelatin or acacia, and lubricating agents, e.g. magnesium stearate, stearic acid or talc.
  • the pharmaceutical composition may be presented e.g. in tablet or capsule form.
  • the preferred route of administration of said pharmaceutical composition is oral administration.
  • the active agent may be present in the pharmaceutical composi ⁇ tion in an amount from 0.1 mg to 10 g, preferably 1 mg to 250 mg, in particular 10 mg to 100 mg.
  • Usual dosages can also be de ⁇ termined on the basis of kg body weight of the patient, for ex ⁇ ample preferred dosages are in the range of 0.01 mg to 10 mg/kg body weight, especially 0.1 to 1 mg/body weight (per administra ⁇ tion session) .
  • the administration may occur e.g. once daily, once every other day, once per week or once every two weeks, es ⁇ pecially once daily.
  • active agents de ⁇ scribed herein can also be administered in salt-form (i.e. as a pharmaceutically acceptable salt of the active agent, such as for instance sunitinib malate) . Accordingly, any mention of an active agent herein shall also include any pharmaceutically ac ⁇ ceptable salt forms thereof.
  • the term "specific for” - as in "molecule A specific for molecule B” - means that molecule A has a binding preference for molecule B compared to other molecules in a patient's body.
  • this entails that molecule A (such as an antibody) has a dissociation constant (also called “affinity") in regard to molecule B (such as the antigen, specifically the binding epitope thereof) that is lower than (i.e. "stronger than") 1000 nM, preferably lower than 100 nM, more preferably lower than 50 nM, even more preferably lower than 10 nM, especially lower than 5 nM.
  • the patient is a mammal, especially a human (male or female) .
  • the patient (who preferably has a cancer as defined herein, and especially has been diagnosed with a can ⁇ cer as defined herein) is in need of the inventive treatment.
  • the patient may be a patient that does not have the cancer but is at risk of developing the cancer.
  • mammary cancer and “breast cancer” are used interchangeably.
  • a patient having a malignant “mammary tu ⁇ mour” is equivalent to the patient having breast cancer.
  • a course of treatment with compound X ends (or starts, respectively) within e.g.
  • courses of treatment may also overlap.
  • the term "over-expressing" or similar in regard to a gene (product) A typically can mean that the expression level of A (as e.g. measured by Western blot or immunohistochemistry) e.g. in a tumour sample is higher than the expression level of an appropriate control (such as healthy tissue of the same type), by a factor of at least 1.2 (i.e. an increase of at least 20%), preferably at least 1.4, more preferably at least 1.6, even more preferably at least 1.8, especially at least 2.0; e.g. in connection with oncogene status such as status of HER-2, ER and Kras .
  • the term "under-expressing" or similar in regard to a gene (product) A typically can mean that the expression level of A (as e.g. measured by Western blot or immunohistochemistry) e.g. in a tumour sample is lower than the expression level of an appropriate control (such as healthy tissue of the same type) , by a factor of at most 0.8 (i.e. a decrease of at least 20%), preferably at most 0.7, more preferably at most 0.6, even more preferably at most 0.5, especially at most 0.25 or even at most 0.1; e.g. in connection with tumour suppressor status such as p53 status.
  • an appropriate control such as healthy tissue of the same type
  • the present invention further relates to the following embod ⁇ iments :
  • Embodiment 1 A pharmaceutical composition comprising an apelin antagonist and/or an apelin receptor antagonist, and further comprising an angiogenesis inhibitor, wherein the angiogen- esis inhibitor is selected from the group of receptor tyrosine kinase (RTK) inhibitors.
  • RTK receptor tyrosine kinase
  • Embodiment 2 A set comprising a first pharmaceutical com ⁇ position, comprising an apelin antagonist and/or an apelin receptor antagonist, and a second pharmaceutical composition, com ⁇ prising an angiogenesis inhibitor, wherein the angiogenesis inhibitor is selected from the group of RTK inhibitors.
  • Embodiment 3 The composition or set according to embodi ⁇ ment 1 or 2, wherein the angiogenesis inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozan- tinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib.
  • the angiogenesis inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozan- tinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib.
  • Embodiment 4 The composition or set according to embodi ⁇ ment 3, wherein the angiogenesis inhibitor is sunitinib.
  • Embodiment 5 The composition or set according to any one of embodiments 1 to 4, wherein the apelin antagonist is selected from the group of anti-apelin antibodies, and/or
  • the apelin receptor antagonist is selected from apelin analogues, preferably a peptide with the sequence QRPRLSHKGPMPA (SEQ ID NO: 14) or N- -acetyl-nona-D-arginine amide (SEQ ID NO: 22) or cyclo (1-6) CRPRLC-KH-cyclo (9-14) CRPRLC (SEQ ID NO: 23), and anti-apelin-receptor antibodies.
  • apelin analogues preferably a peptide with the sequence QRPRLSHKGPMPA (SEQ ID NO: 14) or N- -acetyl-nona-D-arginine amide (SEQ ID NO: 22) or cyclo (1-6) CRPRLC-KH-cyclo (9-14) CRPRLC (SEQ ID NO: 23), and anti-apelin-receptor antibodies.
  • Embodiment 6 An apelin antagonist and/or apelin receptor antagonist for use in the prevention or treatment of cancer in a patient, wherein the apelin antagonist and/or apelin receptor antagonist is administered to the patient, and
  • an angiogenesis inhibitor preferably selected from the group of RTK inhibitors, is administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is administered, or after the apelin antagonist and/or apelin receptor antagonist has been administered .
  • Embodiment 7 An angiogenesis inhibitor for use in the pre ⁇ vention or treatment of cancer in a patient, wherein the angio ⁇ genesis inhibitor is administered to the patient, and wherein an apelin antagonist and/or apelin receptor antagonist, is administered to the patient, in a composition together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibitor is administered, or after the angiogenesis inhibitor has been administered,
  • angiogenesis inhibitor is selected from the group of RTK inhibitors.
  • Embodiment 8 An apelin antagonist and/or apelin receptor antagonist for use in the prevention or treatment of metastasis in a cancer patient, wherein the patient has undergone or is un ⁇ dergoing cancer treatment with an angiogenesis inhibitor, preferably selected from the group of RTK inhibitors.
  • Embodiment 9 An angiogenesis inhibitor for use in the pre ⁇ vention or treatment of metastasis in a cancer patient, wherein the patient has undergone or is undergoing cancer treatment with an apelin antagonist and/or apelin receptor antagonist,
  • angiogenesis inhibitor is selected from the group of RTK inhibitors.
  • Embodiment 10 An apelin antagonist and/or apelin receptor antagonist for use in the treatment of a cancer patient who has resistance or is at risk of developing resistance to anti- angiogenic therapy, preferably anti-angiogenic therapy with an angiogenesis inhibitor selected from the group of RTK inhibi ⁇ tors .
  • Embodiment 11 An angiogenesis inhibitor for use in the treatment of a cancer patient who has resistance or is at risk of developing resistance to anti-angiogenic therapy, wherein the angiogenesis inhibitor is administered to the patient, and wherein an apelin antagonist and/or apelin receptor antagonist, is administered to the patient, in a composition together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibitor is administered, or after the angiogenesis inhibitor has been administered,
  • angiogenesis inhibitor is selected from the group of RTK inhibitors.
  • Embodiment 12 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 11, wherein the angiogenesis inhibi ⁇ tor is selected from the group of sunitinib, sorafenib, pazo- panib, axitinib, cabozantinib, regorafenib, vandetanib, tivoza- nib, cediranib, nintedanib and vatalanib.
  • the angiogenesis inhibi ⁇ tor is selected from the group of sunitinib, sorafenib, pazo- panib, axitinib, cabozantinib, regorafenib, vandetanib, tivoza- nib, cediranib, nintedanib and vatalanib.
  • Embodiment 13 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to embodiment 12, wherein the angiogenesis inhibitor is sunitinib.
  • Embodiment 14 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 13, wherein the apelin antagonist is selected from the group of anti-apelin antibodies and/or,
  • the apelin receptor antagonist is selected from apelin analogues, preferably a peptide with the sequence QRPRLSHKGPMPA (SEQ ID NO: 14) or N- -acetyl-nona-D-arginine amide (SEQ ID NO: 22) or cyclo (1-6) CRPRLC-KH-cyclo (9-14) CRPRLC (SEQ ID NO: 23), and anti-apelin-receptor antibodies.
  • apelin analogues preferably a peptide with the sequence QRPRLSHKGPMPA (SEQ ID NO: 14) or N- -acetyl-nona-D-arginine amide (SEQ ID NO: 22) or cyclo (1-6) CRPRLC-KH-cyclo (9-14) CRPRLC (SEQ ID NO: 23), and anti-apelin-receptor antibodies.
  • Embodiment 15 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 14, wherein the cancer is of epithe ⁇ lial origin and/or selected from breast cancer, lung cancer ovarian cancer, cervical cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine cancer, gastr ⁇ oesophageal cancer, colorectal cancer, glioma, prostate cancer and pancreatic cancer, in particular selected from breast cancer and lung cancer.
  • the cancer is of epithe ⁇ lial origin and/or selected from breast cancer, lung cancer ovarian cancer, cervical cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine cancer, gastr ⁇ oesophageal cancer, colorectal cancer, glioma, prostate cancer and pancreatic cancer, in particular selected from breast cancer and lung cancer.
  • Embodiment 16 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 15, wherein the cancer is HER-2- positive, estrogen-receptor-positive, p53-negative, KRas- positive or combinations thereof.
  • Embodiment 17 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 16, wherein the cancer over- expresses epithelial-mesenchymal transition (EMT) markers, pref ⁇ erably selected from the group of Snail, fibronectin, and TGF- beta, and/or
  • EMT epithelial-mesenchymal transition
  • cancer over-expresses invasiveness-related genes, preferably selected from the group of Met, ILlb, COL1A1 and COL1A2 and/or
  • cancer over-expresses apelin and/or apelin receptor.
  • Embodiment 18 The apelin antagonist and/or apelin receptor antagonist for use according to any one of embodiments 6 to 17, wherein a further chemotherapeutic agent, and/or radiotherapy for the latter three of the following cases, is administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is adminis ⁇ tered, or after the apelin antagonist and/or apelin receptor antagonist has been administered,
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics,
  • the further chemotherapeutic agent is select ⁇ ed from the group of 5-fluorouracil , cisplatin, carboplatin, cy ⁇ clophosphamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vi- norelbine and etoposide, in particular etoposide.
  • Embodiment 19 The angiogenesis inhibitor for use according to any one of embodiments 6 to 17, wherein a further chemothera ⁇ plastic agent, and/or radiotherapy for the latter three of the following cases, is administered to the patient, in a composi ⁇ tion together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibi ⁇ tor is administered, or after the angiogenesis inhibitor has been administered,
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics,
  • the further chemotherapeutic agent is select ⁇ ed from the group of 5-fluorouracil , cisplatin, carboplatin, cy ⁇ clophosphamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vi- norelbine and etoposide, in particular etoposide, and/or
  • angiogenesis inhibitor is selected from the group of RTK inhibitors such as sunitinib.
  • Embodiment 20 The apelin antagonist and/or apelin receptor antagonist for use according to any one of embodiments 6 to 18, wherein a Src tyrosine kinase inhibitor is also administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is adminis ⁇ tered or after the apelin antagonist and/or apelin receptor antagonist has been administered,
  • the Src tyrosine kinase inhibitor is selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib.
  • Embodiment 21 The angiogenesis inhibitor for use according to any one of embodiments 6 to 19, wherein a Src tyrosine kinase inhibitor is also administered to the patient, in a composition together with the angiogenesis inhibitor, in combination with the angiogenesis inhibitor, before the angiogenesis inhibitor is administered or after the angiogenesis inhibitor has been admin ⁇ istered,
  • the Src tyrosine kinase inhibitor is selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib and/or
  • angiogenesis inhibitor is selected from the group of RTK inhibitors such as sunitinib.
  • Embodiment 22 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 21, wherein the patient has an ape ⁇ lin level, preferably a plasma or serum apelin level, higher than a control, and/or the cancer has an apelin or apelin receptor level higher than a control;
  • the apelin level is measured after the pa ⁇ tient has undergone cancer treatment with an angiogenesis inhib ⁇ itor, preferably selected from the group of RTK inhibitors, es- pecially sunitinib; and/or
  • the cancer is selected from breast cancer, lung cancer, ovarian cancer, cervical cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine cancer, gastro-oesophageal cancer, colorectal cancer, glioma, prostate cancer and pancreatic cancer, in particular selected from breast cancer and lung cancer.
  • Embodiment 23 The apelin antagonist and/or apelin receptor antagonist, or the angiogenesis inhibitor, for use according to any one of embodiments 6 to 22, for tumour blood vessel normali ⁇ sation.
  • Embodiment 24 A pharmaceutical composition comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23 and a further chemotherapeutic agent,
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics, preferably selected from the group of 5-fluorouracil , cisplatin, carboplatin, cyclophos ⁇ phamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etoposide, in particular etoposide,
  • composition is for parenteral, especially intravenous, administration.
  • Embodiment 25 A set comprising a first pharmaceutical com ⁇ position comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23 and a second pharmaceutical composition comprising a further chemotherapeutic agent,
  • the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics, preferably selected from the group of 5-fluorouracil , cisplatin, carboplatin, cyclophos ⁇ phamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etoposide, in particular etoposide.
  • Embodiment 26 A pharmaceutical composition comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23, and a Src tyrosine kinase in ⁇ hibitor, preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially da ⁇ satinib,
  • composition is for oral administration.
  • Embodiment 27 A set comprising a first pharmaceutical com ⁇ position comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23 and a second pharmaceutical composition comprising a Src tyrosine ki ⁇ nase inhibitor,
  • Embodiment 28 The pharmaceutical composition of embodiment 24 or 26, further comprising the angiogenesis inhibitor as set forth in any one of embodiments 1 to 23,
  • angiogenesis inhibitor is an RTK inhibi ⁇ tor such as sunitinib.
  • Embodiment 29 The set of embodiment 25 or 27, further com ⁇ prising the angiogenesis inhibitor as set forth in any one of embodiments 1 to 23, wherein the angiogenesis inhibitor is pre ⁇ sent in the first pharmaceutical composition, in the second pharmaceutical composition or in a third pharmaceutical composi ⁇ tion,
  • angiogenesis inhibitor is an RTK inhibi ⁇ tor such as sunitinib.
  • Embodiment 30 A pharmaceutical composition comprising the angiogenesis inhibitor as set forth in any one of embodiments 1 to 23, and a Src tyrosine kinase inhibitor, preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib;
  • a Src tyrosine kinase inhibitor preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib;
  • composition is for oral administration, and/or
  • the apelin antagonist or apelin receptor antagonist as set forth in any one of embodiments 1 to 23 is also administered or has been administered or is subsequently to be administered to the patient, especially wherein the apelin antagonist is an anti-apelin antibody or the apelin receptor antagonist is an an- ti-apelin-receptor antibody.
  • Embodiment 31 A set comprising the angiogenesis inhibitor as set forth in any one of embodiments 1 to 23 and a second pharmaceutical composition comprising a Src tyrosine kinase in ⁇ hibitor preferably selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially da ⁇ satinib ;
  • the apelin antagonist or apelin receptor antagonist as set forth in any one of embodiments 1 to 23 is also administered or has been administered or is subsequently to be administered to the patient, especially wherein the apelin antagonist is an anti-apelin antibody or the apelin receptor antagonist is an an- ti-apelin-receptor antibody.
  • Embodiment 32 The pharmaceutical composition of embodiment 30, further comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23.
  • Embodiment 33 The set of embodiment 31, further comprising the apelin antagonist and/or apelin receptor antagonist as set forth in any one of embodiments 1 to 23, wherein the apelin antagonist and/or apelin receptor antagonist is present in the first pharmaceutical composition, in the second pharmaceutical composition or in a third pharmaceutical composition,
  • the apelin antagonist is an anti-apelin anti ⁇ body or the apelin receptor antagonist is an anti-apelin- receptor antibody.
  • Embodiment 34 The composition or set of any one of embodi ⁇ ments 30 to 33, wherein the angiogenesis inhibitor is an RTK in ⁇ hibitor, preferably selected from the group of sunitinib, soraf- enib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, es ⁇ pecially sunitinib.
  • the angiogenesis inhibitor is an RTK in ⁇ hibitor, preferably selected from the group of sunitinib, soraf- enib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, es ⁇ pecially sunitin
  • Embodiment 35 The composition or set of embodiment 34, wherein the angiogenesis inhibitor sunitinib and the Src tyro ⁇ sine kinase inhibitor is dasatinib.
  • Embodiment 36 The composition or set of any one of embodi ⁇ ments 24 to 35 for use in any one of the uses set forth in em ⁇ bodiments 6 to 23.
  • Embodiment 37 The composition or set for use according to embodiment 36, for use in the prevention or treatment of a can ⁇ cer,
  • the cancer is selected from breast cancer and lung cancer.
  • Embodiment 38 The composition or set for use according to embodiment 36, for use in the prevention or treatment of metas ⁇ tasis in a cancer patient, wherein the patient has undergone or is undergoing cancer treatment with an angiogenesis inhibitor, preferably selected from the group of RTK inhibitors such as sunitinib,
  • the cancer is selected from breast cancer and lung cancer.
  • Embodiment 39 The composition or set for use according to embodiment 36, for use in the treatment of a cancer patient who has resistance or is at risk of developing resistance to anti- angiogenic therapy, preferably anti-angiogenic therapy with an angiogenesis inhibitor selected from the group of RTK inhibitors such as sunitinib,
  • the cancer is selected from breast cancer and lung cancer.
  • Embodiment 40 A chemotherapeutic agent selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics, especially topoisomerase inhibitors ,
  • angiogenesis inhibitor for use in treatment of a cancer, or in prevention or treatment of cancer metastasis, in a cancer patient, wherein the patient has undergone or is undergoing or is to sub ⁇ sequently undergo treatment with an angiogenesis inhibitor, the angiogenesis inhibitor as set forth in any one of embodiments 1 to 23, and wherein the patient has undergone or is undergoing or is to subsequently undergo treatment with an apelin antagonist or apelin receptor antagonist, either antagonist as set forth in any one of embodiments 1 to 23,
  • the patient has undergone said treatment with the angiogenesis inhibitor and said treatment with either antag ⁇ onist, or wherein the patient is undergoing said treatment with the angiogenesis inhibitor and said treatment with either antag ⁇ onist .
  • Embodiment 41 The chemotherapeutic agent for use according to embodiment 40, wherein the agent is selected from the group of 5-fluorouracil , cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etopo ⁇ side, in particular etoposide.
  • the agent is selected from the group of 5-fluorouracil , cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etopo ⁇ side, in particular etoposide.
  • Embodiment 42 The chemotherapeutic agent for use according to embodiment 40 or 41, wherein the angiogenesis inhibitor is selected from the group of RTK inhibitors, preferably from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantin- ib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, especially sunitinib.
  • the angiogenesis inhibitor is selected from the group of RTK inhibitors, preferably from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantin- ib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, especially sunitinib.
  • Embodiment 43 The chemotherapeutic agent for use according to any one of embodiments 40 to 42, wherein the apelin antago ⁇ nist is selected from the group of anti-apelin antibodies, or wherein the apelin receptor antagonist is selected from apelin analogues and anti-apelin-receptor antibodies.
  • Embodiment 44 The chemotherapeutic agent for use according to any one of embodiments 40 to 43, wherein the cancer is se ⁇ lected from breast cancer, lung cancer, ovarian cancer, cervical cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine cancer, gastro-oesophageal cancer, colo ⁇ rectal cancer, glioma, prostate cancer and pancreatic cancer, in particular selected from breast cancer and lung cancer.
  • Embodiment 45 A Src tyrosine kinase inhibitor for use in treatment of a cancer, or in prevention or treatment of cancer metastasis, in a cancer patient,
  • the patient has undergone said treatment with the angiogenesis inhibitor and said treatment with either antag ⁇ onist, or wherein the patient is undergoing said treatment with the angiogenesis inhibitor and said treatment with either antag ⁇ onist .
  • Embodiment 46 The Src tyrosine kinase inhibitor for use ac ⁇ cording to embodiment 45, wherein the Src tyrosine kinase inhib ⁇ itor is selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib.
  • Embodiment 47 The Src tyrosine kinase inhibitor for use ac ⁇ cording to embodiment 45 or 46, wherein the angiogenesis inhibi ⁇ tor is selected from the group of RTK inhibitors, preferably from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, especially sunitinib.
  • the angiogenesis inhibi ⁇ tor is selected from the group of RTK inhibitors, preferably from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib, especially sunitin
  • Embodiment 48 The Src tyrosine kinase inhibitor for use ac ⁇ cording to any one of embodiments 45 to 47, wherein the apelin antagonist is selected from the group of anti-apelin antibodies, or wherein the apelin receptor antagonist is selected from ape ⁇ lin analogues and anti-apelin-receptor antibodies.
  • Embodiment 49 The Src tyrosine kinase inhibitor according to any one of embodiments 45 to 48, wherein the cancer is se ⁇ lected from breast cancer, lung cancer, ovarian cancer, cervical cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine cancer, gastro-oesophageal cancer, colo ⁇ rectal cancer, glioma, prostate cancer and pancreatic cancer, in particular selected from breast cancer and lung cancer.
  • Fig. 1 Human apelin variants.
  • the human APLN gene codes for an apelin preproprotein ("apelin-77") containing a signal peptide in its amino-terminal sequence thus directing apelin in the se ⁇ cretory pathway.
  • the proprotein (“apelin-55”) gives rise to several bioactive carboxy-terminal fragments including apelin-36, apelin-17 and apelin-13.
  • the amino-terminal glutamine of apelin-13 can be post-translationally modified thus creating the pyroglutamate apelin-13 (pyr-apelin-13) which is more pro ⁇ tected from exopeptidase degradation.
  • Fig. 2 Apelin is a prognostic factor in breast and lung cancer
  • Fig. 3 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor further increased survival and reduced tumour burden in breast cancer
  • Anti-angiogenic treatment with sunitinib malate 60mg/kg per dose by gavage, three times a week was started only after cancer onset, established by mammary tumour palpation and followed until the mice were sacrificed when the tumour size was 1 cm 3 , following ethical guidelines
  • b) Kaplan Meier plot for survival in NeuT ; Apln +/+ and NeuT ; Apln _/ ⁇ mice with mammary cancer, control or treated with sunitinib malate after tumour onset (*P ⁇ 0.05; Log rank test; n 7-ll) .
  • Fig. 5 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor did not further reduce angiogen- esis.
  • a) CD31-positive area (percentage) in Neu ; Apln +/+ and Neu ; Apln _/ ⁇ age-matched mammary tumours control or treated with sunitinib malate 4 weeks after tumour onset (*P ⁇ 0.05; T-test; n 6) .
  • Tu ⁇ mours were size-matched at 30-50mm 3 (called "0 days") and fol ⁇ lowed over time.
  • Fig. 6 Apelin regulated adhesion pathways similarly to VEGF.
  • Fig. 7 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor reduced vessel leakage and in ⁇ terstitial pressure, thereby leading to vessel normalisation. Quantification from non-invasive MRI data following over-time NeuT ; Apln +/+ and NeuT ; Apln _/ ⁇ mammary tumours, control or treated with sunitinib malate. Tumours were size-matched and followed over-time to study a) K 2 leakage pre/post contrast and b) T 2 .
  • Fig. 8 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor reduced vessel leakage also in lung cancer, thereby leading to vessel normalisation.
  • GSEA Gene set enrichment analysis
  • Fig. 11 Ablation of apelin (a) and administration of an apelin receptor antagonist (b) have a similar inhibitory effect on tu ⁇ mor growth in vivo: a) Primary tumor growth after orthotopic injection of E0771 mammary cancer cells expressing control shRenilla or shApln into the mammary gland of B6 mice (control Apln+/+ or Apln-/-, respectively) .
  • the upper curve shows tumor growth of the control
  • the lower curve shows reduced tumor growth of E0771 cells (with apelin knocked down) in apelin knockout mice
  • Treatment with the apelin receptor antagonist MM54 also reduces tumor growth.
  • Apelin knockout mice These mice were generated previously and carry a deletion of the apelin gene in the germline (Kuba et al. , 2007) .
  • MMTV-WeuT transgenic mice were used, which carry the activated c-neu oncogene, a major human breast cancer oncogene, driven by a mouse mammary tumour virus (MMTV) promoter (Muller et al . , 1988) . These transgenic mice develop mammary adenocarcinomas that involve the entire epithelium in each gland and are widely used as a model to study breast can ⁇ cer. Tumour onset of mammary tumours was determined by weekly palpation of the mammary glands. In addition, the E0771 metastatic mammary cancer model was also used (Ewens, et al . , 2005) .
  • MMTV mouse mammary tumour virus
  • Lung cancer models Cre-inducible model of K-RasG12D-driven non-small cell lung cancer (NSCLC) combined with p53 floxed (Jackson, 2001), the most prevalent form of lung cancer.
  • NSCLC non-small cell lung cancer
  • the ex ⁇ pression of K-RasG12D is controlled by a Lox-Stop-Lox cassette, which can be removed by Cre recombinase.
  • Intratracheal admin ⁇ istration of adeno- or lenti-viruses expressing Cre was used to specifically induce K-RasG12D expression and p53 deletion in the pneumocytes of the lung (DuPage et al . , 2009a) .
  • Anti-angiogenic treatment with the multimodal RTK inhibitor sunitinib malate (60mg/kg body weight per dose by oral gavage, three times a week) was started only after cancer onset and fol ⁇ lowed until the mice were sacrificed.
  • vascular permeability assay Lysinated labelled dextran (70kDa; Invitrogen, D1818, 1.25mg in lOOuL ddH20) was intrave ⁇ foundedly injected into the tail vein of each tumour-bearing mouse. At 15 minutes post-injection, mice were sacrificed and tumours were harvested, followed by overnight fixation in 4 "6PFA. Whole- mount immunostaining of tumour samples was performed with anti- CD31 (Dianova) followed by goat Alexa 633 secondary antibody. Positive signals were examined by confocal microscopy.
  • Non-invasive MRI was performed on a 15.2 T Bruker system (Bruker BioSpec, Ettlingen Germany) with a 35 mm quadrature birdcage coil. Mice were continuously monitored for tumour oc ⁇ currence by palpation and MRI. When tumours reached 30-50 mm 3 this was set as imaging day 0, and then each tumour was imaged after 2, 4 and 6 weeks. Before imaging, the tail line was in ⁇ serted for delivery of contrast agent (30 gauge needle with sil ⁇ icon tubing) . All animals were anaesthetised with isoflurane (4% induction, maintenance with 1.5%). During imaging, respiration was monitored and isoflurane levels were adjusted if breathing was ⁇ 20 or >60 breaths per minute.
  • tumour volume was calculated by multiplying the slice thickness with the tu ⁇ mour area by an investigator blinded to the treatment group. Im- ageJ was used to calculate T2-values.
  • DSC Dynamic susceptibility contrast
  • a Tl-weighted spin-echo dataset was ac ⁇ quired (0.5 mm thick slices, TR/TE 500/5.8 ms, 117 ⁇ 2 resolu ⁇ tion, 2 NEX) .
  • Perfusion data were processed offline using ImageJ (National Institutes of Health; rsbweb.nih.gov/ij/), and the DSCoMAN plugin (Duke University, https : //dblab . duhs . duke . edu/Wysiwyg/downloads /DSCoMAN_l .0. pdf) .
  • Antibody array pathway analysis For the human phospho-kinase antibody array (R&D Systems) , primary HUVEC (human umbilical vein endothelial cells) were cultured overnight with media sup ⁇ plemented with 0.75% of fetal bovine serum (FBS) followed by 15 minutes of media with 0.5%. The cells were then stimulated in serum-free media with either Apelin Pyrl3 (BACHEM H-4568, 500nM) , human VEGF (Peprotech, 25ng/mL) , both of them or either for 5 minutes. 100 ⁇ g of cell lysate were added to the membrane and incubated overnight at 4°C with gentle agitation, following the manufacturer instructions. Films were scanned and the inten ⁇ sity of the bands quantified using ImageJ.
  • FBS fetal bovine serum
  • RNA of tumours and isolated mammary epithelial cells was prepared using the RNeasy Mini Kit (Qiagen) , according to the manufacturer's instructions.
  • cDNA synthesis was performed using the iScript cDNA synthesis kit (Bio-Rad) .
  • Bioinformatics PolyA-mRNA of large NeuT; Apln-/- and Neu ; Apln+/+ tumours treated or untreated with sunitinib was isolated and the generated libraries were sequenced by 50-bp single-end Illumina mRNA sequencing. Differential expression analysis of aligned reads was performed with DESeq.
  • Pathway en ⁇ richment was evaluated using GSEA (gene set enrichment analy ⁇ sis) . Gene sets with significant enrichment were selected based on a false discovery rate (FDR) q value cut-off of 1%.
  • FDR false discovery rate
  • Example 2 Apelin as a prognostic factor
  • Example 3 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor
  • NSCLC non-small cell lung carcinomas
  • apelin-deficient mice were crossed to a Lox-Stop-Lox-KRas G12D strain together with a conditional p53 allele flanked by LoxP sites (p53 f/f ; KRas ; Apln ⁇ /y hereafter) (Jackson, 2001).
  • Intratracheal administration of adeno-viruses expressing Cre was used to specifically induce KRas G12D expression and delete p53 in pneumoyctes (DuPage et al . , 2009b) .
  • RTK inhibitors have been hampered by the onset of resistance resulting in increased leakiness of the vessels, tumour malig ⁇ nancy and a poor patient outcome with increased metastases (Po- tente et al . , 2011) .
  • the multimodal RTK inhibitor sunitinib malate was administered to NeuT ; Apln ⁇ / ⁇ or NeuT ; Apln +/+ mice (Fig. 3a) and p53 f/f ; KRas ; Apln +/y or p53 f/f ; KRas ; Apln ⁇ /y mice (Fig.
  • Example 4 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor induced tumour vessel normalisa ⁇ tion
  • tumour angiogenesis using immunohistochemical (IHC) CD31 staining and quantification of tumour blood volume overtime by non-invasive magnetic resonance imaging (MRI) showed that apelin ablation alone or treatment with the RTK inhibitor sunitinib alone reduced mammary tumour angiogenesis (Fig. 5a and b) .
  • MRI magnetic resonance imaging
  • apelin ablation alone or treatment with the RTK inhibitor sunitinib alone reduced mammary tumour angiogenesis
  • combination of both apelin targeting and sunitinib treatment did not further diminish tumour angio ⁇ genesis.
  • pathway analysis by phospho-antibody array in primary human endothelial cells (HUVECs) was performed untreated or stimulated with apelin-13, recombinant VEGF or both of them to ⁇ gether (Fig. 5a) .
  • Example 5 Combination of apelin ablation and anti-angiogenic treatment with an RTK inhibitor reduced tumour proliferation, malignancy, EMT and invasiveness
  • the GSEA analysis also revealed a signature of genes positively correlated with sensitivity of breast cancer cells to dasatinib in the combinatory scenario compared to the other groups as well as with expression signa ⁇ tures that predict sensitivity to individual chemotherapeutic drugs (e.g. etoposide) (Figs. 9d and 9e) .
  • a more invasive tumour microenvironment in cancer was correlated with resistance to anti-angiogenic therapy and decreased chemotherapy delivery, and, as shown above, the inventive treatment decreased the invasiveness profile of the tumour.
  • Example 6 Targeting apelin reduced metastasis induced by anti- angiogenic treatment with an RTK inhibitor
  • E0771 cells express ape- lin and APJ, and both were highly induced in tumours.
  • B6 Apln+/+; E0771shRen orthotopically injected control cells in B6 wild-type mice
  • B6 Apln-/- mice B6 Apln-/- mice
  • E0771shApln sunitinib treatment reduced the growth of the E0771 tumour cells in vivo.
  • Example 7 In-vivo comparison of apelin ablation to the administration of an apelin receptor antagonist
  • E0771 mammary cancer cells expressing either a control short-hairpin RNA (shRenilla) or a short- hairpin RNA specific for apelin (shApln) were injected orthotop ⁇ ically in the mammary gland of B6 mice which were either Apln+/+, i.e. wild-type (in the case of the control) or Apln-/-, i.e. apelin-ablated (in the case of shApln) .
  • Tumor volume was assessed at various points in time after the injection and was significantly reduced in the apelin-ablated scenario.
  • E0771 mammary cancer cells were injected orthotopically in the mammary gland of Apln+/+ B6 mice which were then treated with the apelin receptor antagonist MM54 (0.4mg/Kg by intraperitoneal injection three times a week from day 8) or left untreated.
  • MM54 is cyclo ( 1- 6) CRPRLC-KH-cyclo ( 9-14 ) CRPRLC (SEQ ID NO: 23), first disclosed in Macaluso et al . , 2011. Tumor volume was assessed at various points in time after the injection and was significantly reduced by treatment with the apelin receptor antagonist MM54.
  • a female patient is diagnosed with a malignant mammary tu ⁇ mour of stage IIIA and grade 3.
  • Oncogene status of the tumour is: estrogen-receptor negative, progesterone-receptor negative and HER2-positive (3+ as assessed by immunohistochemistry) .
  • the tumour responds only insufficiently to neoadjuvant treatment with trastuzumab, despite remaining HER2-positive . Therefore, the inventive treatment regimen is started (overall duration: 10 months) : The patient is orally administered 50 mg sunitinib mal- ate daily, on a four weeks on, two weeks off dosing schedule.
  • a single intravenous dose (210 mg corresponding to 3 mg/kg body weight) of humanized monoclonal anti-apelin-receptor antibody H2aM9232N is administered.
  • the antibody treatment is repeated every two weeks at a lower dose of 105 mg corresponding to 1.5 mg/kg body weight.
  • etoposide 50mg per day for 5 days, repeated every 4 weeks is added to the reg ⁇ imen.
  • the inventive treatment inhibits the formation of metasta ⁇ ses. After 6 months, tumour volume is reduced sufficiently for allowing removal of the tumour by breast-conserving surgery.
  • a male patient is diagnosed with a malignant non-small- cell lung cancer of stage IIIB.
  • the oncogene status of the tu ⁇ mour is p53-negative, KRas-positive, assessed by immunohisto ⁇ chemistry.
  • the patient is not a surgical candidate.
  • the patient is prescribed the inventive treatment regimen, specifically a concurrent cytotoxic chemotherapy/radiotherapy regimen with an angiogenesis inhibitor and an apelin antagonist as an adjuvant therapy.
  • Carboplatin AUC 2 IV is administered weekly for 7 weeks, and paclitaxel is given during the same 7 weeks at 50 mg/m2 IV on a weekly basis.
  • External beam radiotherapy is begun at the same time as the chemotherapy and is delivered 5 days a week, also for 7 weeks.
  • the patient is also orally administered 5 mg of the RTK inhibitor axitinib twice daily on an on-going continuous schedule that continues as a monotherapy after the completion of the radiochemotherapy treatment.
  • an antibody treatment is begun with a single intravenous dose of 3 mg/kg body weight of humanized monoclonal anti-apelin antibody specific for the epitope PRLSHKG (SEQ ID NO: 12) disclosed in WO 2013/012855 Al, to be repeated on a twice weekly basis at 1.5 mg/kg body weight.
  • the size of the tumour is reduced sufficient ⁇ ly for the patient to be now considered a surgical candidate.
  • Alexiadou et al . "Differences in plasma apelin and visfatin levels between patients with type 1 diabetes mellitus and healthy subjects and response after acute hyperglycemia and insulin administration.” Hormones (Athens) 11.4 (2012): 444-50. Angelova, et al . "Apelin and Testosterone Levels in Men with Metabolic Syndrome.” Open Journal of Endocrine and Metabolic Diseases 2014 (2014) .
  • Gyorffy, et al . (2013) Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer.
  • Hammond, et al "American Society of Clinical Oncology/College of American Pathologists guideline recommendations for
  • Apelin is a novel angiogenic factor in retinal endothelial cells. Biochemical and Biophysical Research Communications 325, 395-400.
  • Lamouille, et al "Molecular mechanisms of epithelial- mesenchymal transition.” Nature reviews. Molecular cell biology 15.3 (2014) : 178.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention relève du domaine du traitement anti-angiogénique. Des efforts sont nécessaires pour réduire ou surmonter le problème de résistance du cancer aux traitements anti-angiogéniques, par exemple les traitements basés sur le sunitinib, inhibiteur de récepteurs à tyrosine kinase (RTK). La présente invention concerne donc un agent qui peut être associé à un traitement anti-angiogénique afin de réduire ou surmonter le problème de résistance audit traitement anti-angiogénique. La présente invention concerne donc une composition ou un ensemble pharmaceutique comprenant un antagoniste de l'apeline et/ou un antagoniste du récepteur de l'apeline, et un inhibiteur de l'angiogenèse. L'inhibiteur de l'angiogenèse est un inhibiteur de RTK, de préférence le sunitinib. L'antagoniste de l'apeline peut être un anticorps anti-apeline. L'antagoniste du récepteur de l'apeline peut être un analogue peptidique de l'apeline ou un anticorps anti-récepteur de l'apeline. En outre, l'invention concerne des méthodes de traitement du cancer, en particulier de traitement du cancer du sein ou du poumon, basées sur un antagoniste de l'apeline et/ou un antagoniste du récepteur de l'apeline et un inhibiteur de l'angiogenèse.
PCT/EP2017/058316 2016-04-07 2017-04-07 Association d'un antagoniste de l'apeline et d'un inhibiteur de l'angiogenèse pour le traitement du cancer Ceased WO2017174758A1 (fr)

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* Cited by examiner, † Cited by third party
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US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
CN112165953A (zh) * 2018-04-05 2021-01-01 剑桥企业有限公司 用作爱帕琳肽受体拮抗剂的化合物
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
CN114099642A (zh) * 2021-11-12 2022-03-01 南通大学 基因Apln在制备治疗与细胞成血管有关疾病药物中的应用
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

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* Cited by examiner, † Cited by third party
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Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033976A1 (fr) 1997-12-24 1999-07-08 Takeda Chemical Industries, Ltd. Polypeptide, son procede de production et son utilisation
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
WO2002092573A2 (fr) 2001-05-16 2002-11-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de src et autres proteine kinases
US6534524B1 (en) 1999-07-02 2003-03-18 Agouron Pharmaceuticals, Inc. Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
WO2003068228A1 (fr) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Urees aryliques a activite inhibitrice d'angiogenese
US20060045880A1 (en) 2004-08-23 2006-03-02 Krieg Paul A Methods for modulating angiogenesis and apoptosis with apelin compositions
US7105348B2 (en) 2000-10-31 2006-09-12 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US7141581B2 (en) 1999-07-02 2006-11-28 Agouron Pharmaceuticals, Inc. Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
WO2007014707A1 (fr) 2005-08-01 2007-02-08 F. Hoffmann-La Roche Ag Derives benzylamino heterocycliques, leurs procedes de fabrication et leur utilisation en tant qu'agents pharmaceutiques
WO2010053545A2 (fr) 2008-11-04 2010-05-14 Anchor Therapeutics, Inc. Composés de récepteur apj
WO2013012855A1 (fr) 2011-07-18 2013-01-24 Amgen Inc. Protéines de liaison à antigène de l'apéline et leurs utilisations
US20140005181A1 (en) 2012-06-21 2014-01-02 Sanford-Burnham Medical Research Institute Small molecule antagonists of the apelin receptor for the treatment of disease
WO2014044738A1 (fr) 2012-09-21 2014-03-27 Sanofi Dérivés d'amide d'acide benzimidazole-carboxylique utilisés comme modulateurs du récepteur apj
WO2015077491A1 (fr) 2013-11-20 2015-05-28 Regeneron Pharmaceuticals, Inc. Modulateurs d'aplnr et leurs utilisations
WO2015140296A2 (fr) 2014-03-20 2015-09-24 Centre National De La Recherche Scientifique (Cnrs) Utilisation de composés inhibant la signalisation d'apeline/apj/gp130 pour le traitement du cancer

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033976A1 (fr) 1997-12-24 1999-07-08 Takeda Chemical Industries, Ltd. Polypeptide, son procede de production et son utilisation
US6534524B1 (en) 1999-07-02 2003-03-18 Agouron Pharmaceuticals, Inc. Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
US7141581B2 (en) 1999-07-02 2006-11-28 Agouron Pharmaceuticals, Inc. Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
US7105348B2 (en) 2000-10-31 2006-09-12 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
WO2002092573A2 (fr) 2001-05-16 2002-11-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de src et autres proteine kinases
WO2003068228A1 (fr) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Urees aryliques a activite inhibitrice d'angiogenese
US20060045880A1 (en) 2004-08-23 2006-03-02 Krieg Paul A Methods for modulating angiogenesis and apoptosis with apelin compositions
WO2007014707A1 (fr) 2005-08-01 2007-02-08 F. Hoffmann-La Roche Ag Derives benzylamino heterocycliques, leurs procedes de fabrication et leur utilisation en tant qu'agents pharmaceutiques
WO2010053545A2 (fr) 2008-11-04 2010-05-14 Anchor Therapeutics, Inc. Composés de récepteur apj
WO2013012855A1 (fr) 2011-07-18 2013-01-24 Amgen Inc. Protéines de liaison à antigène de l'apéline et leurs utilisations
US20140005181A1 (en) 2012-06-21 2014-01-02 Sanford-Burnham Medical Research Institute Small molecule antagonists of the apelin receptor for the treatment of disease
WO2014044738A1 (fr) 2012-09-21 2014-03-27 Sanofi Dérivés d'amide d'acide benzimidazole-carboxylique utilisés comme modulateurs du récepteur apj
WO2015077491A1 (fr) 2013-11-20 2015-05-28 Regeneron Pharmaceuticals, Inc. Modulateurs d'aplnr et leurs utilisations
WO2015140296A2 (fr) 2014-03-20 2015-09-24 Centre National De La Recherche Scientifique (Cnrs) Utilisation de composés inhibant la signalisation d'apeline/apj/gp130 pour le traitement du cancer

Non-Patent Citations (73)

* Cited by examiner, † Cited by third party
Title
ALEXIADOU ET AL.: "Differences in plasma apelin and visfatin levels between patients with type 1 diabetes mellitus and healthy subjects and response after acute hyperglycemia and insulin administration", HORMONES (ATHENS, vol. 11.4, 2012, pages 444 - 450
ALMAGRO ET AL.: "Humanization of antibodies", FRONT BIOSCI, vol. 13.1, 2008, pages 1619 - 1633
ANGELOVA ET AL.: "Apelin and Testosterone Levels in Men with Metabolic Syndrome", OPEN JOURNAL OF ENDOCRINE AND METABOLIC DISEASES, 2014
APTE ET AL.: "The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions", CANCER AND METASTASIS REVIEWS, vol. 25.3, 2006, pages 387 - 408, XP019447665, DOI: doi:10.1007/s10555-006-9004-4
BERGERS ET AL.: "Modes of resistance to anti-angiogenic therapy", NATURE REVIEWS CANCER, vol. 8.8, 2008, pages 592 - 603, XP055095845, DOI: doi:10.1038/nrc2442
BERTA ET AL.: "Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis", J THORAC ONCOL, vol. 5, 2010, pages 1120 - 1129, XP055189317, DOI: doi:10.1097/JTO.0b013e3181e2c1ff
BHARGAVA ET AL.: "Development of second-generation VEGFR tyrosine kinase inhibitors: current status", CURRENT ONCOLOGY REPORTS, vol. 13.2, 2011, pages 103 - 111
BIRCH ET AL.: "Antibody production", ADVANCED DRUG DELIVERY REVIEWS, vol. 58.5, 2006, pages 671 - 685, XP024892148, DOI: doi:10.1016/j.addr.2005.12.006
BOXERMAN ET AL.: "Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. AJNR", AMERICAN JOURNAL OF NEURORADIOLOGY, vol. 27, no. 4, 2006, pages 859 - 867, XP002457319
BUKOWSKI ET AL.: "Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma", FRONT ONCOL, vol. 2, 2012, pages 13
CHAPMAN ET AL.: "The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR 1", BIOCHEMISTRY AND CELL BIOLOGY, vol. 92.6, 2014, pages 431 - 440
CHAVES-ALMAGRO ET AL.: "Apelin receptors: From signaling to antidiabetic strategy", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 763, 2015, pages 149 - 159, XP029278829, DOI: doi:10.1016/j.ejphar.2015.05.017
CHOW ET AL.: "Sunitinib: from rational design to clinical efficacy", JOURNAL OF CLINICAL ONCOLOGY, vol. 25.7, 2007, pages 884 - 896
COX ET AL.: "Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo", DEVELOPMENTAL BIOLOGY, vol. 296, 2006, pages 177 - 189, XP024943852, DOI: doi:10.1016/j.ydbio.2006.04.452
DEL TORO ET AL.: "Identification and functional analysis of endothelial tip cell-enriched genes", BLOOD, vol. 116, 2010, pages 4025 - 4033
DUPAGE ET AL.: "Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase", NAT PROTOC, vol. 4, 2009, pages 1064 - 1072
EISENHAUER ET AL.: "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1", EUROPEAN JOURNAL OF CANCER, vol. 45.2, 2009, pages 228 - 247, XP025841550, DOI: doi:10.1016/j.ejca.2008.10.026
EWENS ET AL.: "Distant metastasis from subcutaneously grown E0771 medullary breast adenocarcinoma.", ANTICANCER RESEARCH, vol. 25, no. 6B, 2005, pages 3905 - 3915
GERBIER ET AL.: "New structural insights into the apelin receptor: identification of key residues for apelin binding", THE FASEB JOURNAL, vol. 29.1, 2015, pages 314 - 322
GHERARDI ET AL.: "Targeting MET in cancer: rationale and progress", NATURE REVIEWS CANCER, vol. 12.2, 2012, pages 89 - 103, XP055044370, DOI: doi:10.1038/nrc3205
GOEL ET AL.: "P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer", CELL REPORTS, vol. 14.9, 2016, pages 2193 - 2208
GOTINK; VERHEUL: "Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?", ANGIOGENESIS, vol. 13.1, 2010, pages 1 - 14
GRAEVEN ET AL.: "Modulation of angiogenesis and tumourigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor", CANCER RESEARCH, vol. 61, 2001, pages 7282 - 7290
GYORFFY ET AL.: "Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer", PLOS ONE, vol. 8, no. 12, 2013, pages E82241
HAMMOND ET AL.: "American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version", ARCHIVES OF PATHOLOGY LABORATORY MEDICINE, vol. 134.7, 2010, pages E48 - E72
HANAHAN; WEINBERG: "Hallmarks of Cancer: The Next Generation.", CELL, vol. 144, 2011, pages 646 - 674, XP028185429, DOI: doi:10.1016/j.cell.2011.02.013
HARVEY ET AL.: "Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer", JOURNAL OF CLINICAL ONCOLOGY, vol. 17.5, 1999
HO-YEN ET AL.: "The clinical and functional significance of c-Met in breast cancer: a review", REAST CANCER RESEARCH, vol. 17.1, 2015, pages 52
INCIO ET AL.: "Abstract LB-203: Obesity promotes resistance to anti-VEGF therapy in breast cancer via pro-inflammatory and angiogenic pathways", CANCER RESEARCH, vol. 75.15, 2015, pages LB-203
JACKSON: "Analysis of lung tumour initiation and progression using conditional expression of oncogenic K-ras", GENES DEV, vol. 15, 2001, pages 3243 - 3248, XP002584752
JAYSON ET AL.: "Antiangiogenic therapy in oncology: current status and future directions", THE LANCET, 2016
JELTSCH ET AL.: "Receptor tyrosine kinase-mediated angiogenesis", COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, vol. 5.9, 2013, pages A009183
JUDIT BERTA ET AL: "Apelin Expression in Human Non-small Cell Lung Cancer: Role in Angiogenesis and Prognosis", JOURNAL OF THORACIC ONCOLOGY, 1 August 2010 (2010-08-01), United States, pages 1120 - 1129, XP055189317, Retrieved from the Internet <URL:http://ovidsp.ovid.com/ovidweb.cgi?T=JS&NEWS=n&CSC=Y&PAGE=fulltext&D=ovft&AN=01243894-201008000-00004> [retrieved on 20150513], DOI: 10.1097/JTO.0b013e3181e2c1ff *
KALIN ET AL.: "Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumour angiogenesis", DEVELOPMENTAL BIOLOGY, vol. 305, 2007, pages 599 - 614, XP022057233, DOI: doi:10.1016/j.ydbio.2007.03.004
KALIN ET AL: "Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis", DEVELOPMENTAL BIOLOGY, ACADEMIC PRESS, AMSTERDAM, NL, vol. 305, no. 2, 2 May 2007 (2007-05-02), pages 599 - 614, XP022057233, ISSN: 0012-1606, DOI: 10.1016/J.YDBIO.2007.03.004 *
KALLURI; ZEISBERG: "Fibroblasts in cancer", NATURE REVIEWS CANCER, vol. 6.5, 2006, pages 392 - 401, XP002538033, DOI: doi:10.1038/NRC1877
KASAI, A. ET AL.: "Apelin is a novel angiogenic factor in retinal endothelial cells", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 325, 2004, pages 395 - 400, XP004626806, DOI: doi:10.1016/j.bbrc.2004.10.042
KASAI, A. ET AL.: "Retardation of Retinal Vascular Development in Apelin-Deficient Mice", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 28, 2008, pages 1717 - 1722
KAWAMATA ET AL.: "Molecular properties of apelin: tissue distribution and receptor binding", BIOCHIMICA ET BIOPHYSICA ACTA (BBA)-MOLECULAR CELL RESEARCH, vol. 1538.2, 2001, pages 162 - 171, XP004235731, DOI: doi:10.1016/S0167-4889(00)00143-9
KIDOYA ET AL.: "Biology of the apelin-APJ axis in vascular formation", J BIOCHEM., 2012
KIDOYA ET AL.: "Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis", EMBO J, vol. 27, 2008, pages 522 - 534, XP055171559, DOI: doi:10.1038/sj.emboj.7601982
KRISTY J GOTINK ET AL: "Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?", ANGIOGENESIS, KLUWER ACADEMIC PUBLISHERS, DO, vol. 13, no. 1, 11 December 2009 (2009-12-11), pages 1 - 14, XP019786303, ISSN: 1573-7209 *
KUBA ET AL.: "Impaired Heart Contractility in Apelin Gene Deficient Mice Associated With Aging and Pressure Overload", CIRCULATION RESEARCH, vol. 101, 2007, pages E32 - E42
LAMOUILLE ET AL.: "Molecular mechanisms of epithelial-mesenchymal transition", NATURE REVIEWS. MOLECULAR CELL BIOLOGY, vol. 15.3, 2014, pages 178
LARSEN ET AL.: "Improved method for predicting linear B-cell epitopes", IMMUNOME RESEARCH, vol. 2.1, 2006, pages 1
LEE ET AL.: "Modification of the terminal residue of apelin-13 antagonizes its hypotensive action", ENDOCRINOLOGY, vol. 146.1, 2005, pages 231 - 236, XP002741939, DOI: doi:10.1210/en.2004-0359
LUCCHINI ET AL.: "Early and multifocal tumours in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice", CANCER LETT., vol. 64, 1992, pages 203 - 209
MACALUSO ET AL.: "Discovery of a competitive apelin receptor (APJ) antagonist.", CHEMMEDCHEM, vol. 6.6, 2011, pages 1017 - 1023, XP055072896, DOI: doi:10.1002/cmdc.201100069
MALONEY ET AL.: "Discovery of 4-oxo-6-((pyrimidin-2-ylthio) methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22.21, 2012, pages 6656 - 6660
MARTIN TA ET AL.: "Madame Curie Bioscience Database", 2000, LANDES BIOSCIENCE, article "Cancer Invasion and Metastasis: Molecular and Cellular Perspective"
MIZUNO, H. ET AL.: "PrognoScan: a new database for meta-analysis of the prognostic value of genes", BMC MEDICAL GENOMICS, vol. 2, no. 1, 2009, pages 18, XP021060649, DOI: doi:10.1186/1755-8794-2-18
MULLER ET AL.: "Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene", CELL, vol. 54, 1988, pages 105 - 115, XP023913134, DOI: doi:10.1016/0092-8674(88)90184-5
PHAN, VERNON T. ET AL.: "Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 110.15, 2013, pages 6079 - 6084
POTENTE ET AL.: "Basic and Therapeutic Aspects of Angiogenesis", CELL, vol. 146, 2011, pages 873 - 887, XP028295703, DOI: doi:10.1016/j.cell.2011.08.039
PUFFER ET AL.: "Expression and coreceptor function of APJ for primate immunodeficiency viruses", VIROLOGY, vol. 276.2, 2000, pages 435 - 444, XP004435851, DOI: doi:10.1006/viro.2000.0557
RAKHA ET AL.: "Updated UK Recommendations for HER2 assessment in breast cancer", JOURNAL OF CLINICAL PATHOLOGY, vol. 68.2, 2015, pages 93
RAYALAM ET AL.: "A putative role for apelin in the etiology of obesity", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 368.3, 2008, pages 815 - 819, XP022504675, DOI: doi:10.1016/j.bbrc.2008.02.008
RAYALAM ET AL.: "Emerging role of apelin as a therapeutic target in cancer: a patent review", RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY, vol. 6.3, 2011, pages 367 - 372, XP009163660, DOI: doi:10.2174/157489211796957856
RAYALAM SRUJANA ET AL: "Emerging role of apelin as a therapeutic target in cancer: a patent review", RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY, BENTHAM SCIENCE, SHARJAH, UNITED ARAB EMIRATES, vol. 6, no. 3, 1 September 2011 (2011-09-01), pages 367 - 372, XP009163660, ISSN: 2212-3970, DOI: 10.2174/157489211796957856 *
REAUX ET AL.: "Distribution of apelin-synthesizing neurons in the adult rat brain", NEUROSCIENCE, vol. 113.3, 2002, pages 653 - 662
ROSKOSKI: "Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors", PHARMACOLOGICAL RESEARCH, vol. 94, 2015, pages 9 - 25, XP029583891, DOI: doi:10.1016/j.phrs.2015.01.003
S C SORLI ET AL: "Apelin is a potent activator of tumour neoangiogenesis", ONCOGENE, vol. 26, no. 55, 11 June 2007 (2007-06-11), GB, pages 7692 - 7699, XP055282483, ISSN: 0950-9232, DOI: 10.1038/sj.onc.1210573 *
SAINT-GENIEZ ET AL.: "Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels.", MECH. DEV., vol. 110, 2002, pages 183 - 186, XP002992963, DOI: doi:10.1016/S0925-4773(01)00558-5
SCHENONE ET AL.: "SRC kinase inhibitors: An update on patented compounds", CURRENT MEDICINAL CHEMISTRY, vol. 18.33, 2011, pages 5061 - 5078
SORLI ET AL.: "Apelin is a potent activator of tumour neoangiogenesis", ONCOGENE, vol. 26, 2007, pages 7692 - 7699, XP055282483, DOI: doi:10.1038/sj.onc.1210573
SULZMAIER ET AL.: "FAK in cancer: mechanistic findings and clinical applications", NATURE REVIEWS CANCER, vol. 14.9, 2014, pages 598 - 610
SUN ET AL.: "Design, synthesis, and evaluations of substituted 3-[(3-or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42.25, 1999, pages 5120 - 5130
TATEMOTO ET AL.: "Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 251, 1998, pages 471 - 476, XP002101895, DOI: doi:10.1006/bbrc.1998.9489
VAN CUTSEM ET AL.: "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer", NEW ENGLAND JOURNAL OF MEDICINE, vol. 360.14, 2009, pages 1408 - 1417, XP055013583, DOI: doi:10.1056/NEJMoa0805019
WANG ET AL.: "Immunohistochemical localization of apelin in human normal breast and breast carcinoma", JOURNAL OF MOLECULAR HISTOLOGY, vol. 39.1, 2008, pages 121 - 124
ZHANG, YU ET AL.: "Low plasma apelin in newly diagnosed type 2 diabetes in Chinese people", DIABETES CARE, vol. 32, no. 12, 2009, pages E150
ZHIQIN WANG ET AL: "Immunohistochemical localization of apelin in human normal breast and breast carcinoma", JOURNAL OF MOLECULAR HISTOLOGY, KLUWER ACADEMIC PUBLISHERS, DO, vol. 39, no. 1, 6 September 2007 (2007-09-06), pages 121 - 124, XP019573284, ISSN: 1567-2387 *
ZHOU ET AL.: "Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1.", VIROLOGY, vol. 312.1, 2003, pages 196 - 203, XP004441770, DOI: doi:10.1016/S0042-6822(03)00185-5

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10150760B2 (en) 2016-05-03 2018-12-11 Amgen Inc. Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
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CN112165953B (zh) * 2018-04-05 2025-03-04 剑桥企业有限公司 用作爱帕琳肽受体拮抗剂的化合物
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor
CN114099642A (zh) * 2021-11-12 2022-03-01 南通大学 基因Apln在制备治疗与细胞成血管有关疾病药物中的应用

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